Clinical Approach to Abnormal Liver Enzyme
Liver Cirrhosis Rx
Prevalence of abnormal liver enzyme tests during asymptomatic
screening is not uncommon, estimated to be 1-4% by some author (Scand J
Gastroenterol 1986;21:106 Hultcrantz R), and is up to one-third of patients
screened by others (Mayo Clin Proc 1996; 71:1089 Patrick S. Kamath).
symptoms of liver disease as anorexia, nausea, vomiting, fatigue, right upper
quadrant abdominal pain, jaundice, pruritis, low grade fever, dark-colored
urine, clay-colored stools.
past history of hepatitis, alcohol or drug/medication use, transfusion, travel,
unusual diet (raw oyster, mushroom, etc.), sexual history.
family history of liver disease as Gilbert's syndrome, Wilson's disease,
hemochromatosis, or alpha 1-antitrypsin deficiency, viral hepatitis.
Other medical illnesses like cardiac disease, inflammatory bowel disease,
diabetes, arthritis, thyroid diseases, etc.
Signs of liver disease as jaundice, palmar erythema, spider nevi, parotid
enlargement, ascites, hepatosplenomegaly, encephalopathy, abdominal tenderness;
Kayser-Fleischer rings of Wilson's disease, etc.
Clinical Assessment of the elevated ALT, AST Patients
History & Physical Examination, & repeat to confirm elevation of
liver enzyme tests
If asymptomatic, & no elevated alk.phosphatase or bilirubin, may recheck
in 3-6 months.
If ALT >3-5x or duration > 6months, approach according to the disease
suspected (risk factors)
Alcohol or drug related: recheck after 6-8 weeks of abstinence.
Viral hepatitis: check for hepatitis B or C serology markers.
Nonalcoholic steatohepatitis: liver ultrasound or CT scan.
Autoimmune: ANA, smooth muscle antibody, antimitochondrial antibody.
Wilson's disease: slit lamp eye exam, copper & ceruloplasmin level.
Hemochromatosis: ferritins, % iron saturation
Alpha 1-antitrypsin deficiency: alpha 1 antitrypsin level
Consider liver biopsy if still abnormal.
Interpretation of abnormal
aminotransferase/transaminase (ALT, AST) elevation:
It suggests hepatocellular damage.
Elevation of AST > ALT, especially if > 2x, suggests alcoholic hepatitis.
Elevation of AST < ALT is usually seen in viral hepatitis.
In choledocholithiasis, an AST increase is the earlist abnormality detected,
& usually < 5X. The AST increase is typically transient &
returns to normal within 72 hours.
In cholangitis, the AST increase can be up to 10-fold.
In viral and drug-induced hepatitis, the AST, ALT levels steadily increase
and peak in the low thousands range within 7-14 days. In uncomplicated
viral hepatitis, the transaminases return to normal in about 6 weeks.
In ischemic hepatitis, the transaminase abruptly increase within 24 hours
and may even be higher than 10,000 IU/L.
In acetaminophen overdose or in herpes simplex hepatitis, the transaminase
increases greater than 10,000 IU/L are also noted.
Many medications can cause increases in AST, such as acetaminophen, NSAID,
ACE-inhibitors, nicotinic acid, isoniazid, sulfonamides, erythromycin,
anti-fungal agents as griseofulvin & fluconazole.
Alcoholic or Nonalcoholic Steatohepatitis
(NASH) & hyperthyroidism & hypothyroidism can also
cause increased AST< ALT.
Clinical Assessment of the elevated alkaline
phosphatase & GGT Patients
If alk.phos < 2X, < 6 months, & asymptomatic low risk patients,
recheck test in 3-6 months.
If disease is suspected, check ultrasound or CT scan of liver & biliary
tract, then ERCP or liver biopsy as needed.
If alk.phos > 2X, > 6 months, or symptomatic, check liver/bilirary
if there is biliary dilatation, consider ERCP.
if no biliary dilatation, consider antimitochondrial antibody & liver
If suspect alcohol or drug-related: recheck after 6-8 weeks of abstinence.
If suspect viral hepatitis: viral serology markers.
If suspect primary biliary cirrhosis: antimitochondrial antibody.
If suspect primary sclerosing cholangitis: ERCP.
Then liver biopsy if indicated.
Interpretation Abnormal Alkaline Phosphatase
It suggest hepatobililary disease, can be divided into
1. biliary obstruction,
2. intrahepatic cholestasis (drug or viral hepatitis)
or extrahepatic cholestasis (gallstones or tumors),
3. infiltrative process: localized lesion within the
liver (hepatocellular carcinoma or metastatic liver cancer)
or patchy involvement within the liver (metastatic cancer
or granulomatous disease),
4. chronic inflammation involving the bile ducts: primary
sclerosing cholangitis, or primary biliary cirrhosis.
It is also elevated in bone disease, pregnancy, hyperthyroidism, lymphoma,
hypernephroma, cardiac failure. Patients with blood group O and B who
are secretors can have increased alkaline phosphatase after eating a fatty
meal because of the release of the intestinal enzyme, therefore the test
must be performed in fasting patients.
Gamma-glutamyltransferase (GGT) test is recommended to confirm the hepatic
origin of the elevated alk.phosphatase. It is the most sensitive marker
of biliary tract disease.
Normally, the total bilirubin level is less than 1.1 mg/DL, & approximately
70% is indirect (unconjugated) bilirubin.
Unconjugated hyperbilirubinemia (> 80% of the total bilirubin is indirect)
suggests hemolysis or Gilbert's syndrome. The bilirubin level is usually
< 6.0 mg/DL.;
Conjugated hyperbilirubinemia (> 50% of the total bilirubin is direct)
suggests hepatocellular dysfunction or cholestasis.
When the bilirubin level is > 25-30 mg/dL, extrahepatic cholestasis is
an unlikely diagnosis, because the predominantly conjugated bilirubin is
water soluble, it is excreted easily by the kidney in extrahepatic cholestasis.
Hepatocellular diseases (increased ALT,
Common: Chronic viral hepatitis, alcoholic liver disease, nonalcoholic
steatohepatitis, medication toxicity, autoimmune hepatitis, genetic
Less Common: Wilson's disease, Alpha 1-antitrypsin deficiency
Cholestatic diseases (elevated alk.phosphatase
Common: Biliary obstruction (gallstones, tumor), drug hepatotoxicity,
neoplasms, primary biliary cirrhosis, primary sclerosing cholangitis
Less Common: autoimmune cholangiopathy, sarcoidosis
Medications with potential for
Hepatocellular abnormalities: allopurinol (granuloma), azathioprine
(veno-occlusive disease), NSAID, hydralazine (granuloma), isoniazid, methotrexate
(fibrosis), methyldopa, nitrufurantoin (autoimmune-like), quinidine (granuloma).
Cholestatic abnormalities: Phynytoin (mononucleosis-like synd), sulfa
drugs, oral contraceptive, estrogens, erythromycin estolate, captopril,
chlorpromazine, anabolic steroids, amoxicillin-clavulanate (Augmentin), &
other penicillin derivatives.
Fatty liver (with or without hepatocellular abnormalities): tetracycline,
valproid acid, corticosteroids, amiodarone (phospholipidosis).
Nonalcoholic Steatohepatitis (fatty
liver): perhaps the most common cause of mildly elevated liver enzymes
in the US. It is commonly seen in patients with obesity, diabetes,
hyperlipidemia, medications, & jejunoileal bypass surgery.
Primary Biliary Cirrhosis: antimitochondrial
antibody, elevated alk.phosphatase
Autoimmune liver disease: ANA
>1:160 especially homogeneous pattern, smooth muscle antibody positivity.
Wilson's disease: low serum copper & cerulopasmin levels, low
uric acid, Kayser-Fleischer rings.
Hemochromatosis: transferrin saturation >60% in men, >50% in
women, & if the ferritin levels >1,000 ug/L.
Viral hepatitis: positivity of viral serologic markers as Hepatitis
A-IgM, Hepatitis BsAg, Hepatitis BcAb (IgM), Hepatitis C Ab.
Extrahepatic cholestasis: diagnosed by liver sonography or CT scan,
Infiltrative liver disease: diagnosed by liver biopsy.
Cleveland Clin J Med 3/1998; 65:150 - Zobair Younossi
Mayo Clin Proc 11/1996;71:1089 - Patrick S. Kamath
REF: DynaMed 2009
Abnormal liver function tests - differential
Updated 2009 Mar 20 02:05 PM: elevated serum alanine aminotransferase may
be associated with liver disease mortality (Gastroenterology 2009 Feb)
AST and ALT actually reflect hepatocellular injury rather than liver function
which is better reflected by albumin and prothrombin time
Elevated AST/ALT (Hepatocellular Injury)
aspartate aminotransaminase (AST) produced by liver, heart, skeletal muscle,
kidney, brain, red blood cell
alanine aminontransaminsase (ALT) produced by liver (more specific for liver
acute injury signified by moderate-to-marked increase (5-10 times upper limit
levels > 1,000 units/L correspond to severe liver necrosis or fulminant
elevated serum alanine aminotransferase may be associated with liver disease
Alcohol use disorder (AST/ALT ratio = 2 with AST < 300 units/L and
gamma-glutamyl-transpeptidase [GGT] 2 times normal levels)
viral hepatitis (aminotransferases peak before jaundice appears)
Hepatitis C (may have more prominent increase in liver enzymes than other
Epstein-Barr virus (infectious mononucleosis)
nonalcoholic fatty liver disease (steatosis/steatohepatitis)
autoimmune hepatitis (liver enzymes mildly elevated)
hemochromatosis (check serum ferritin, iron and transferrin saturation)
alpha-1 antitrypsin (AAT) deficiency
hepatic metastatic disease
acute fatty liver of pregnancy
obesity - may have mildly elevated ALT and AST
unexplained aminotransferase elevation associated with higher body mass index
in study of 15,676 adults in United States 1988-1994 (Am J Gastroenterol
Muscle injury - AST elevation
idiopathic inflammatory myopathy
diabetes mellitus - 9.5% patients with type 1 diabetes and 12.1% patients
with type 2 diabetes had elevated serum alanine aminotransaminase (ALT) levels
in study of 1,353 patients with diabetes who did not have excessive alcohol
consumption (QJM 2006 Dec;99(12):871)
Macro-AST (complex between normal AST and immunoglobulin)
dantrolene sodium (Dantrium)
HMG-CoA reductase inhibitors (statins)
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac, piroxicam
Herbs and supplements:
Chaparral leaf (Larrea tridentata)
Germander (Teucrium chamaedrys)
Jin bu huan
Mistletoe (Viscum album)
Senna (Cassia angustifolia)
beryllium - associated with granulomatous hepatitis
copper - associated with granulomatous hepatitis